Clinical OperationsGlossary Term
ICH E6(R3) Section 4.5
Protocol deviations are departures from the approved protocol that may or may not impact participant safety or data integrity, while protocol violations are a subset of deviations that significantly impact participant safety, data quality, or scientific validity of the trial.
The distinction between protocol deviations and violations reflects the spectrum of severity and impact that departures from protocol requirements may have on trial conduct. All violations are deviations, but not all deviations rise to the level of violations. Understanding this distinction is essential for appropriate categorization, reporting, and corrective action, as regulatory authorities and ethics committees have different expectations for how various categories of non-compliance should be managed and reported.
Protocol deviations encompass any departure from the approved protocol, regardless of cause or impact. Minor deviations, such as a visit occurring slightly outside the protocol-specified window due to scheduling constraints, may have minimal impact on data quality or participant welfare. Major deviations represent more significant departures that may affect data interpretability or participant safety. Protocol violations represent the most serious category, involving departures that significantly impact participant rights, safety, or welfare, or that substantially affect the integrity, accuracy, or reliability of study data.
Classification systems vary across sponsors, institutions, and regulatory jurisdictions, but common factors considered in categorization include impact on participant safety, effect on data quality or interpretability, whether the deviation was intentional or inadvertent, and whether it represents a pattern of non-compliance. Important and major deviations typically require expedited reporting to the IRB/IEC and sponsor. Recurrent deviations at a site may indicate systemic issues requiring intensive intervention or, in serious cases, termination of the site's participation in the trial.
Minor deviation
"The Week 12 visit was conducted on Day 86 instead of the protocol-specified Day 84, representing a minor timing deviation documented in the deviation log but not requiring expedited reporting given the minimal impact on data quality."
Protocol violation
"Administration of study drug to a participant who did not meet eligibility criteria was classified as a protocol violation due to its significant impact on both participant safety, as the individual had a contraindicated condition, and data integrity, requiring immediate IRB notification and root cause analysis."
A systematic approach to identifying, investigating, and addressing the root causes of quality problems or non-conformances, implementing corrections to resolve existing issues, and establishing preventive measures to reduce the likelihood of recurrence.
The documented chronological history of the handling, transfer, and storage of investigational products, biological samples, or other controlled materials, establishing accountability at each step from origin to final disposition.
The system of documentation and procedures that accounts for all investigational product received at a site, dispensed to participants, returned by participants, and remaining in inventory, ensuring complete traceability throughout the trial.
The process of officially registering a qualified participant into a clinical trial after confirming eligibility and obtaining informed consent, marking the point at which the individual becomes a study subject.
A systematic evaluation conducted before trial initiation to determine whether a clinical trial can be successfully conducted at a particular site or in a specific region, considering factors such as patient population, site capabilities, and regulatory environment.
ICH E6(R3) Section 4.5
Protocol deviations are departures from the approved protocol that may or may not impact participant safety or data integrity, while protocol violations are a subset of deviations that significantly impact participant safety, data quality, or scientific validity of the trial.
The distinction between protocol deviations and violations reflects the spectrum of severity and impact that departures from protocol requirements may have on trial conduct. All violations are deviations, but not all deviations rise to the level of violations. Understanding this distinction is essential for appropriate categorization, reporting, and corrective action, as regulatory authorities and ethics committees have different expectations for how various categories of non-compliance should be managed and reported.
Protocol deviations encompass any departure from the approved protocol, regardless of cause or impact. Minor deviations, such as a visit occurring slightly outside the protocol-specified window due to scheduling constraints, may have minimal impact on data quality or participant welfare. Major deviations represent more significant departures that may affect data interpretability or participant safety. Protocol violations represent the most serious category, involving departures that significantly impact participant rights, safety, or welfare, or that substantially affect the integrity, accuracy, or reliability of study data.
Classification systems vary across sponsors, institutions, and regulatory jurisdictions, but common factors considered in categorization include impact on participant safety, effect on data quality or interpretability, whether the deviation was intentional or inadvertent, and whether it represents a pattern of non-compliance. Important and major deviations typically require expedited reporting to the IRB/IEC and sponsor. Recurrent deviations at a site may indicate systemic issues requiring intensive intervention or, in serious cases, termination of the site's participation in the trial.
Minor deviation
"The Week 12 visit was conducted on Day 86 instead of the protocol-specified Day 84, representing a minor timing deviation documented in the deviation log but not requiring expedited reporting given the minimal impact on data quality."
Protocol violation
"Administration of study drug to a participant who did not meet eligibility criteria was classified as a protocol violation due to its significant impact on both participant safety, as the individual had a contraindicated condition, and data integrity, requiring immediate IRB notification and root cause analysis."
A systematic approach to identifying, investigating, and addressing the root causes of quality problems or non-conformances, implementing corrections to resolve existing issues, and establishing preventive measures to reduce the likelihood of recurrence.
The documented chronological history of the handling, transfer, and storage of investigational products, biological samples, or other controlled materials, establishing accountability at each step from origin to final disposition.
The system of documentation and procedures that accounts for all investigational product received at a site, dispensed to participants, returned by participants, and remaining in inventory, ensuring complete traceability throughout the trial.
The process of officially registering a qualified participant into a clinical trial after confirming eligibility and obtaining informed consent, marking the point at which the individual becomes a study subject.
A systematic evaluation conducted before trial initiation to determine whether a clinical trial can be successfully conducted at a particular site or in a specific region, considering factors such as patient population, site capabilities, and regulatory environment.